Methods and compounds for treating proliferative diseases

1. A compound of Formula I

wherein

A and B are independently O or S;

R 1 is hydrogen, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, hydroxy, hydroxy(C 1 –C 4 )alkyl, halogen, cyano, halo(C 1 –C 4 )alkyl, (C 1 –C 4 alkyl)-NR 5 R 6 , or (C 1 –C 4 alkyl)-(C 1 –C 4 alkyl ester of an amino acid residue);

R 2 is hydrogen, C 1 –C 4 alkyl, hydroxy(C 1 –C 4 )alkyl, (C 1 –C 4 alkyl)-NR 5 R 6 , (C 1 –C 4 alkyl)-C(O)NR 5 R 6 , or (C 1 –C 4 alkyl)-(C 1 –C 4 alkyl ester of an amino acid residue);

R 3 and R 3 ′ are independently hydrogen, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, or halogen;

R 4 is hydrogen or C 1 –C 4 alkyl;

R 5 is independently at each occurrence hydrogen, C 1 –C 4 alkyl, hydroxy(C 1 –C 4 )alkyl, (C 1 –C 4 alkyl)-NR 7 R 8 , C(O)NR 7 R 8 , C(O)—(C 1 –C 4 alkyl), or optionally substituted C 3 –C 8 cycloalkyl; and R 6 is independently at each occurrence hydrogen or C 1 –C 4 alkyl;

R 7 and R 8 are independently at each occurrence hydrogen or C 1 –C 4 alkyl;

or a pharmaceutically acceptable salt thereof.

2. A method for the treatment of antiproliferative diseases in a mammal selected from the group consisting of breast cancer, colorectal cancer, head and neck carcinomas, esophageal cancer, soft tissue carcinoma, osteosarcoma, hepatoblastomas, non-small cell lung cancer, prostate cancer, and ovarian cancer comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I

wherein

A and B are independently O or S;

R 1 is hydrogen, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, hydroxy, hydroxy(C 1 –C 4 )alkyl, halogen, cyano, halo(C 1 –C 4 )alkyl, (C 1 –C 4 alkyl)-NR 5 R 6 , or (C 1 –C 4 alkyl)-(C 1–4 alkyl ester of an amino acid residue);

R 2 is hydrogen, C 1 –C 4 alkyl, hydroxy(C 1 –C 4 )alkyl, (C 1 –C 4 alkyl)-NR 5 R 6 , (C 1 –C 4 alkyl)-C(O)NR 5 R 6 , or (C 1 –C 4 alkyl)-(C 1 –C 4 alkyl ester of an amino acid residue);

R 3 and R 3 ′ are independently hydrogen, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, or halogen;

R 4 is hydrogen or C 1 –C 4 alkyl;

R 5 is independently at each occurrence hydrogen, C 1 –C 4 alkyl, hydroxy(C 1 –C 4 )alkyl, (C 1 –C 4 alkyl)-NR 7 R 8 , C(O)NR 7 R 8 , C(O)—(C 1 –C 4 alkyl), or optionally substituted C 3 –C 8 cycloalkyl; and R 6 is independently at each occurrence hydrogen or C 1 –C 4 alkyl;

R 7 and R 8 are independently at each occurrence hydrogen or C 1 –C 4 alkyl;

or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising a compound of Formula I

wherein

A and B are independently O or S;

R 1 is hydrogen, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, hydroxy, hydroxy(C 1 –C 4 ) alkyl, halogen cyano, halo(C 1 –C 4 )alkyl, (C 1 –C 4 alkyl)-NR 5 R 6 , or (C 1 –C 4 alkyl)-(C 1 –C 4 alkyl ester of an amino acid residue);

R 2 is hydrogen, C 1 –C 4 alkyl, hydroxy(C 1 –C 4 )alkyl, (C 1 –C 4 alkyl)-NR 5 R 6 , (C 1 –C 4 alkyl)-C(O)NR 5 R 6 , or (C 1 –C 4 alkyl)-(C 1 –C 4 alkyl ester of an amino acid residue);

R 3 and R 3 ′ are independently hydrogen, C 1 –C 4 alkyl, C 1 –C 4 alkoxy, or halogen;

R 4 is hydrogen or C 1 –C 4 alkyl;

R 5 is independently at each occurrence hydrogen, C 1 –C 4 alkyl, hydroxy(C 1 –C 4 )alkyl, (C 1 –C 4 alkyl)-NR 7 R 8 , C(O)NR 7 R 8 , C(O)—(C 1 –C 4 alkyl), or optionally substituted C 3 –C 8 cycloalkyl; and R 6 is independently at each occurrence hydrogen or C 1 –C 4 alkyl;

R 7 and R 8 are independently at each occurrence hydrogen or C 1 –C 4 alkyl;

or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier, diluent or excipient.

4. A compound according to claim 1 wherein A and B are both O.

5. A compound according to claim 1 wherein R 3 and R 3 ′ are both hydrogen.

6. A compound according to claim 1 wherein R 4 is methyl.

7. A compound according to any one of claims 4 – 6 wherein R 1 is (C 1 –C 4 )-NR 5 R 6 .

8. A compound according to any one of claims 4 – 6 wherein R 1 is methoxy.